1-Helicobacter pylori gastritis Associated diseases: -chronic gastritis (90% of chronic antral gastritis) - peptic ulcer (stomach, duodenal) - gastric carcinoma - gastric MALT lymphoma

Pathogenesis of H. pylori gASTRITIS Features that are linked to H.pylori virulence: Flagella (allow motility in viscus mucus) Adhesins (adherence to surface foveolar cells) Urease Protect bacteria directly from acidic PH toxic compounds(ammonium chloride, monochloramine) Toxins (epithelial damage) vacuolating toxin called VacA, which are regulated by the cytotoxin-associated gene A (CagA)

Increased gastric acid secretion H. pylori infection is the most important condition in the pathogenesis of peptic ulcer The infection is present in 90% of persons with duodenal ulcers and in about 70% of those with gastric ulcers Bacterial urease and toxins (which is encoded by CagA gene) cause gastric mucosal damage and may be involved in ulcer or cancer development. Protease induces mucosal damage and breaks the mucus glycoprotein, predisposing to inflammation which continues the mucosal injury Increased gastric acid secretion .

Gastric Carcinoma Risk factors and Pathogenesis: 1. Atrophic gastritis with intestinal metaplasia 2. Adenoma: Up to 30% of gastric adenomas harbor carcinoma at the time of diagnosis. 3. After gastrectomy for a benign disease , there is an increased incidence of gastric carcinoma in the remaining gastric stump (hypochlorhydria, bile reflux, chronic gastritis) 4. H. pylori infection: Increases the risk of chronic gastritis-associated intestinal-type gastric cancer 5. EBV infection:10% of gastric cancer are associated with EBV infection 6. Mutations -CDH1 gene (which codes for E-cadherin impacted in IC adhesion)) are associated with familial diffuse gastric cancer (HDGC)……Loss of E- cadherin key step in diffuse gastric carcinoma development -ABC genes in (FAP) : inc. risk of intestinal type gastric cancer - β-catenin gene : intestinal type 7- Diet generating nitrites

Differences between intestinal and diffuse gastric carcinomas Gastric adenocarcinoma Type Intestinal type Diffuse type Etiology ● H.pylori ● Chronic gastritis/ atrophy/ intestinal metaplasia ● Some cases; mutation in APC & β-catenin. ● Idiopathic/familial ● No precursor lesions ● Mutation of CDH1 gene Gross Fungating mass, ulcer Diffuse infiltrating Microscopic ● Glands ● Signet ring cells ● Poorly differentiated Prognosis Better Poor

COLONIC ADENOCARCINOMA Pathogenesis: Diet: Low vegetable fiber intake, high content of refined carbohydrate and high fat content increase the risk of cancer. Pre-existing adenoma and ulcerative colitis. Genetic factors. - Adenoma-carcinoma sequence; inherited mutation of APC gene, followed by mutation of K-RAS, and P53. - Microsatellite instability pathway (short repeating DNA sequence regions); in patients with defects in DNA mismatch repair genes responsible for detection, excision, repair of DNA errors during replication (Hereditary non polyposis colon cancer)

GIST Features of malignancy ( Prognosis) Malignancy is characterized by local invasion and metastases, usually to the liver,  peritoneum and omentum. Features suggesting malignancy or associated with poorer prognosis include: size (>5 cm) High mitotic activity Tumor necrosis Site: malignant behavior less commonly seen in gastric tumors than those of small intestine

GIST The importance of recognition of a molecular defect in GISTs -Drugs targeted to the tumor cells (Targeted therapy)by imatinib ; tyrosine kinase inhibitor of c- KIT and PDGFRA - Diagnostic markers:c-KIT product/CD117 is expressed immunohistochemically

Pathogenesis of inflammatory bowel disease: Genetics+ intestinal microbiota+intestinal epithelial dysfunction+ altered mucosal immune response Several non confirmed factors are claimed as: 1.Genetic factors; mutations in certain genes regulating the immune response are found to be associated with Crohn's disease (NOD2) 2. T-cell dysfunction; affecting mucosal immune response 3.Epithelial defects; as abnormal Paneth cells (dec.antimicrobial peptides) in Crohn's disease 4- Intestinal microbiota 5- Immune mediated damage; to the intestine, suggested by the chronic recurrent nature of the process and by the occurrence of systemic manifestation of autoimmune disease Transepithelial flux of luminal bacterial components activate immune responses in a genetically susceptible host, with release of TNF and other mediators direct epith. to increase the tight junction permeability Furtherly inc. the flux of luminal material

Pathophysiology of malabsorption Malabsorption results from disturbances in at least one of the four phases of nutrient absorption: 1- Intraluminal digestion; in which proteins, carbohydrates and fats are broken down into absorbable forms 2- Terminal digestion; which involves the hydrolysis of carbohydrates and peptides by disaccharidases and peptidases respectively, in the brush border of the small intestinal mucosa 3- Transepithelial transport; in which nutrients, fluid and electrolytes are transported across and processed within the small intestinal epithelium 4- Lymphatic transport of absorbed lipids

Celiac disease Gluten-sensitive enteropathy or non tropical sprue Pathogenesis: Enviromental factor : Gliadin peptide, resistant to digestion by proteases Genetic factor: +ve family history, close association with class II HLA-DQ2, HLA-DQ8 genetic locus in most of the patients Immune response: CD+4 T cells: -deamidated gliadin interacts with HLA-DQ2or HLA-DQ8 on antigen presenting cell and be presented to CD4+T cells - They produce IFNγ ……mucosal tissue damage - B cell response with formation of antigliadin, anti tissue trans- glutaminase CD8+ T cells: deamidated gliadin ++IL-15 +++activation & proliferationof intraepithelial CD8+ cells (NKG2D) …..cytotoxic and kill the stressly induced enterocytes

Histological & Serological Diagnosis Celiac disease Microscopic (non specific): Second part of duodenum or proximal jejunum (diagnostic) Increased number of intraepithelial CD8+ T cells - Crypt hyperplasia Villous atrophy …..loss of mucosal and brush border surface area……malabsorption???? - Lamina propria : increased eosinophils, mast cells, plasma cells Histological & Serological Diagnosis

Defects in malabsorptive diseases : Defects in malabsorptive diseases Disease Intra-luminal digestion Terminal Digestion Trans-epithelial Transport Lymphatic transport Celiac disease   + Tropical sprue Chronic pancreatitis Cystic fibrosis Disaccharidase Deficiency Whipple disease Abetalipo-proteinemia Parasitic gastroenteritis IBD